Mecr, the mitochondrial trans-2-enoyl-CoA reductase, is a key enzyme in mitochondrial fatty acid synthesis (mtFAS) pathway. MtFAS is essential for various cellular functions, including respiratory function, as it generates precursors for lipoic acid synthesis and may produce long-chain fatty acids crucial for mitochondrial function [4].

Mutations in human Mecr are associated with multiple neurodegenerative conditions. Homozygous pathogenic variants in Mecr (e.g., p.Arg258Trp) cause an LHON-like optic neuropathy, presenting with sudden and painless visual loss at a young age, partial recovery, and persistent central scotoma [1]. In Drosophila, loss of Mecr function leads to lethality, and neuronal loss of Mecr results in progressive neurodegeneration, along with a defect in Fe-S cluster biogenesis, increased iron levels, and elevated ceramide levels [2]. In humans, Mecr-deficient fibroblasts also show elevated ceramide levels and impaired iron homeostasis [2]. In mice, Mecrfl/fl; Cd4cre mice have reduced effector and memory T cells, and Mecr-deficient T cells have decreased mitochondrial respiration, reduced TCA intermediates, accumulated intracellular iron, and are more sensitive to ferroptosis, showing fitness disadvantages in inflammatory, tumor, and infection models [3].

In conclusion, Mecr is vital for mtFAS, which impacts multiple biological processes. Studies using genetic models such as Drosophila and mice have revealed its role in neurodegeneration, iron and ceramide metabolism, and T-cell function. The discovery of Mecr-related neurodegenerative diseases, like the LHON-like optic neuropathy, underscores the importance of Mecr in maintaining normal neural and immunological functions [1,2,3].

References:

1. Fiorini, Claudio, Degiorgi, Andrea, Cascavilla, Maria Lucia, Baruffini, Enrico, Caporali, Leonardo. 2023. Recessive MECR pathogenic variants cause an LHON-like optic neuropathy. In Journal of medical genetics, 61, 93-101. doi:10.1136/jmg-2023-109340. https://pubmed.ncbi.nlm.nih.gov/37734847/

2. Dutta, Debdeep, Kanca, Oguz, Byeon, Seul Kee, Pandey, Akhilesh, Bellen, Hugo J. 2023. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. In Nature metabolism, 5, 1595-1614. doi:10.1038/s42255-023-00873-0. https://pubmed.ncbi.nlm.nih.gov/37653044/

3. Steiner, KayLee K, Young, Arissa C, Patterson, Andrew R, Mogilenko, Denis, Rathmell, Jeffrey. 2024. Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.07.08.602554. https://pubmed.ncbi.nlm.nih.gov/39026793/

4. Rahman, M Tanvir, Koski, M Kristian, Panecka-Hofman, Joanna, Hiltunen, J Kalervo, Autio, Kaija J. 2023. An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration. In Nature communications, 14, 619. doi:10.1038/s41467-023-36358-7. https://pubmed.ncbi.nlm.nih.gov/36739436/